A dual targeting anti-inflammatory prodrug of niflumic acid: combating oxidative mucosal damage and cancer cell proliferation

Nonsteroidal anti-inflammatory drugs (NSAIDs) like niflumic acid (NFA) provide effective pain relief but frequently cause severe gastrointestinal complications. This investigation developed and evaluated a novel prodrug conjugate combining NFA with methyl ferulate to enhance therapeutic efficacy while minimizing gastric toxicity. The prodrug (NFM) was synthesized through esterification using dicyclohexylcarbodiimide coupling chemistry, yielding 91.32% with improved lipophilicity (log P: 4.32 and 3.11). Comprehensive characterization employed spectroscopic techniques, hydrolysis studies, and protein binding assays. The conjugate demonstrated pH-dependent stability, remaining stable in acidic gastric conditions but releasing 77% active drug in intestinal fluid, following first-order kinetics (t₁/₂: 229.8 minutes). Significantly reduced protein binding (78.8% and 92.3%) enhanced bioavailability potential. In vitro cytotoxicity against MCF-7 breast cancer cells revealed moderate anticancer activity (IC ₅₀ : 39.21 µM). Animal studies confirmed excellent safety profile with LD ₅₀ exceeding 2000 mg/kg. Anti-inflammatory evaluation using carrageenan-induced paw edema showed superior sustained activity, achieving 70.07% inhibition at six hours compared to 49.63% for NFA. Remarkably, ulcerogenic studies revealed dramatic gastric safety improvement, with significantly reduced ulcer index compared to parent drug. Biochemical analysis demonstrated preserved gastric wall mucus (234.12 and 184.53 µg/mg protein), reduced lipid peroxidation (12.86 and 31.15 nM MDA/mg protein), and restored antioxidant enzyme levels. Histopathological examination confirmed normal gastric architecture in prodrug treated animals versus erosive lesions with NFA treatment. This dual-targeting approach successfully decoupled anti-inflammatory benefits from gastrointestinal toxicity, presenting a promising therapeutic strategy for safer NSAID therapy.